PROJECT SUMMARY ? Project 3 Modifiable risk factors for breast cancer include low physical activity, alcohol consumption, high body mass index after menopause, low intake of specific nutrients, and possibly tobacco smoke exposure. Evidence supporting the effects of these factors largely comes from studying populations at average risk. Women who are at substantially higher risk for breast cancer (either due to presence of a high-risk gene mutation, a personal history of benign breast disease, a strong family history, or a high score on a clinical risk prediction model) comprise an important clinical population, and it is not clear which of the modifiable risk factors above would be most effective to target for preventing disease in this group. Our project will measure the impact of lifestyle and behavior on breast cancer development by studying two intermediate phenotypes: mammographic breast density, and a novel panel of breast cancer-associated microRNAs. Our project will use the unique High Risk Breast Program (HRBP) cohort at the University of Vermont Medical Center. This longitudinal cohort study has enrolled high-risk women since 2003, with questionnaire data and peripheral blood samples collected at enrollment and every four years thereafter, and active follow-up for breast cancer. We will use the rich HRBP questionnaire data to characterize the modifiable lifestyle/behavioral risk factors listed above. In our first aim, we will collect multiple digital mammography images for all members of the cohort and use a cutting-edge image analysis tool to quantify mammographic breast density on a continuous scale, and model changes in density as a function of lifestyle and behavior. In our second aim, we will quantify 25 breast cancer-associated microRNAs in peripheral blood samples, and model the impact of lifestyle and behavior on their expression. We will consider lifestyle and behavioral factors that are associated with both high breast density and with deleterious microRNA expression to be robust targets for preventive intervention in high-risk women.